Patching up the crypt: Innate immune cells orchestrate intestinal regeneration

Innate lymphoid cells (ILCs) are critical effectors of innate immunity and facilitate homeostasis as well as sustained adaptive immune responses, in particular to pathological infections. Recently, ILCs have emerged as novel orchestrators of tissue remodeling after injury, in the skin, thymus and intestine. In the intestine, group 3 innate lymphoid cells (ILC3s) and their IL-22 production are critical to maintain local crypt stem cells from T cell mediated killing in graft-versus-host (GVHD) disease, yet their mechanisms of action are not completely understood. Intestinal regeneration relies on the continuous replacement of the damaged epithelium by local stem cells, that are contained within a niche in the crypts of Lieberkühn. Interestingly, in mammals, hundreds of lymphoid clusters, namely cryptopatches and containing ILC3s, dendritic cells (DCs) and stromal cells, locate adjacent to the intestinal crypts. We hypothesized that cryptopatches play an important role in intestinal regeneration by conveying damage-associated signals to epithelial stem cell regulation. We set out to elucidate whether interactions between innate immune cells in cryptopatches and intestinal stem cells are significant to enhance mucosal healing, with the ultimate goal of improving epithelial barrier function in pathological conditions, such as alimentary mucositis and inflammatory bowel disease. This thesis untangles the importance of innate immune cells in driving epithelial responses to tissue damage and underscores the mechanisms by which ILC3s fine-tune stem cell responses to ensure epithelial regeneration, likely together with stromal cells and myeloid cells in cryptopatches.